This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhai, Y. Articles by Cho, K. R. Search for Related Content PubMed PubMed Citation Articles by Zhai, Y. Articles by Cho, K. R.

Expression of Membrane Type 1 Matrix Metalloproteinase Is Associated with Cervical Carcinoma Progression and Invasion

Departments of ¹ Pathology and ² Internal Medicine and ³ Comprehensive Cancer Center, University of Michigan Medical School and ⁴ Biostatistics Department, University of Michigan School of Public Health, Ann Arbor, Michigan; ⁵ Epidemiology and Cancer Registration Unit, Catalan Institute of Oncology, Hospital Duran i Reynals, Barcelona, Spain; and ⁶ Instituto Nacional de Cancerologia, Bogota, Colombia

Requests for reprints: Kathleen R. Cho, Department of Pathology, University of Michigan Medical School, 5401 LSI, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216. Phone: 734-764-1549; Fax: 734-647-7950; E-mail: kathcho{at}umich.edu.

Membrane type 1 matrix metalloproteinase (MT1-MMP) is frequently expressed by cancer cells and is believed to play an important role in cancer cell invasion and metastasis. However, little is known about the role of MT1-MMP in mediating invasiveness of cervical cancer cells. In this study, we examined MT1-MMP expression in 58 primary human cervical tissue specimens, including normal cervix, low-grade squamous intraepithelial lesions (LSIL), high-grade SILs (HSIL), and invasive carcinomas. We also evaluated MT1-MMP, MMP-2, and tissue inhibitor of metalloproteinase-2 expression in several cervical cancer–derived cell lines, human papillomavirus (HPV)–immortalized keratinocytes, and keratinocytes derived from a LSIL. Using in situ hybridization techniques to study the cervical tissue specimens, we found that MT1-MMP expression increases with cervical tumor progression (Spearman correlation coefficient = 0.66; P < 0.0001, exact test). Specifically, MT1-MMP expression is very low or absent in normal cervix and LSILs, is readily detectable in HSILs, and is very strongly expressed in nearly all invasive carcinomas. Most but not all cervical cancer–derived cell lines also expressed significant levels of MT1-MMP and MMP-2. Constitutive expression of exogenous MT1-MMP in cervical carcinoma–derived cells and HPV-immortalized keratinocytes with low endogenous levels of MT1-MMP induced invasiveness in collagen I, but this effect was not observed in LSIL-derived keratinocytes. Our results show that MT1-MMP is a key enzyme mediating cervical cancer progression. However, MT1-MMP alone is not always sufficient for inducing keratinocyte invasiveness at least in the collagen I invasion assay used in this study. Further studies of gene expression in preinvasive and invasive cervical cancers should assist with identification of additional critical factors mediating cervical cancer progression.

This article has been cited by other articles:

				N. M. Moss, Y. I. Wu, Y. Liu, H. G. Munshi, and M. S. Stack Modulation of the Membrane Type 1 Matrix Metalloproteinase Cytoplasmic Tail Enhances Tumor Cell Invasion and Proliferation in Three-dimensional Collagen Matrices J. Biol. Chem., July 24, 2009; 284(30): 19791 - 19799. [Abstract] [Full Text] [PDF]

				N. M. Moss, Y. Liu, J. J. Johnson, P. Debiase, J. Jones, L. G. Hudson, H. G. Munshi, and M. S. Stack Epidermal Growth Factor Receptor-Mediated Membrane Type 1 Matrix Metalloproteinase Endocytosis Regulates the Transition between Invasive versus Expansive Growth of Ovarian Carcinoma Cells in Three-Dimensional Collagen Mol. Cancer Res., June 1, 2009; 7(6): 809 - 820. [Abstract] [Full Text] [PDF]

				M. A. Lafleur, D. Xu, and M. E. Hemler Tetraspanin Proteins Regulate Membrane Type-1 Matrix Metalloproteinase-dependent Pericellular Proteolysis Mol. Biol. Cell, April 1, 2009; 20(7): 2030 - 2040. [Abstract] [Full Text] [PDF]

				T. Ludwig, S. M. Theissen, M. J. Morton, and M. J. Caplan The Cytoplasmic Tail Dileucine Motif LL572 Determines the Glycosylation Pattern of Membrane-type 1 Matrix Metalloproteinase J. Biol. Chem., December 19, 2008; 283(51): 35410 - 35418. [Abstract] [Full Text] [PDF]

				S. Yoshida, N. Kajitani, A. Satsuka, H. Nakamura, and H. Sakai Ras Modifies Proliferation and Invasiveness of Cells Expressing Human Papillomavirus Oncoproteins J. Virol., September 1, 2008; 82(17): 8820 - 8827. [Abstract] [Full Text] [PDF]

				C. Nyalendo, E. Beaulieu, H. Sartelet, M. Michaud, N. Fontaine, D. Gingras, and R. Beliveau Impaired tyrosine phosphorylation of membrane type 1-matrix metalloproteinase reduces tumor cell proliferation in three-dimensional matrices and abrogates tumor growth in mice Carcinogenesis, August 1, 2008; 29(8): 1655 - 1664. [Abstract] [Full Text] [PDF]

				M. Ouyang, S. Lu, X.-Y. Li, J. Xu, J. Seong, B. N. G. Giepmans, J. Y.-J. Shyy, S. J. Weiss, and Y. Wang Visualization of Polarized Membrane Type 1 Matrix Metalloproteinase Activity in Live Cells by Fluorescence Resonance Energy Transfer Imaging J. Biol. Chem., June 20, 2008; 283(25): 17740 - 17748. [Abstract] [Full Text] [PDF]

				S. D'Alessio, G. Ferrari, K. Cinnante, W. Scheerer, A. C. Galloway, D. F. Roses, D. V. Rozanov, A. G. Remacle, E.-S. Oh, S. A. Shiryaev, et al. Tissue Inhibitor of Metalloproteinases-2 Binding to Membrane-type 1 Matrix Metalloproteinase Induces MAPK Activation and Cell Growth by a Non-proteolytic Mechanism J. Biol. Chem., January 4, 2008; 283(1): 87 - 99. [Abstract] [Full Text] [PDF]

				Y. Zhai, R. Kuick, B. Nan, I. Ota, S. J. Weiss, C. L. Trimble, E. R. Fearon, and K. R. Cho Gene Expression Analysis of Preinvasive and Invasive Cervical Squamous Cell Carcinomas Identifies HOXC10 as a Key Mediator of Invasion Cancer Res., November 1, 2007; 67(21): 10163 - 10172. [Abstract] [Full Text] [PDF]

				D. Gius, M. C. Funk, E. Y. Chuang, S. Feng, P. C. Huettner, L. Nguyen, C. M. Bradbury, M. Mishra, S. Gao, B. M. Buttin, et al. Profiling Microdissected Epithelium and Stroma to Model Genomic Signatures for Cervical Carcinogenesis Accommodating for Covariates Cancer Res., August 1, 2007; 67(15): 7113 - 7123. [Abstract] [Full Text] [PDF]

				C. Nyalendo, M. Michaud, E. Beaulieu, C. Roghi, G. Murphy, D. Gingras, and R. Beliveau Src-dependent Phosphorylation of Membrane Type I Matrix Metalloproteinase on Cytoplasmic Tyrosine 573: ROLE IN ENDOTHELIAL AND TUMOR CELL MIGRATION J. Biol. Chem., May 25, 2007; 282(21): 15690 - 15699. [Abstract] [Full Text] [PDF]

				Y. Feng, G. T. Bommer, Y. Zhai, A. Akyol, T. Hinoi, I. Winer, H. V. Lin, K. M. Cadigan, K. R. Cho, and E. R. Fearon Drosophila split ends Homologue SHARP Functions as a Positive Regulator of Wnt/{beta}-Catenin/T-Cell Factor Signaling in Neoplastic Transformation Cancer Res., January 15, 2007; 67(2): 482 - 491. [Abstract] [Full Text] [PDF]

				A. G. Remacle, A. V. Chekanov, V. S. Golubkov, A. Y. Savinov, D. V. Rozanov, and A. Y. Strongin O-Glycosylation Regulates Autolysis of Cellular Membrane Type-1 Matrix Metalloproteinase (MT1-MMP) J. Biol. Chem., June 23, 2006; 281(25): 16897 - 16905. [Abstract] [Full Text] [PDF]